Gene expression in blood changes rapidly in neutrophils and monocytes after ischemic stroke in humans: a microarray study.

Ischemic brain and peripheral white blood cells release cytokines, chemokines and other molecules that activate the peripheral white blood cells after stroke. To assess gene expression in these peripheral white blood cells, whole blood was examined using oligonucleotide microarrays in 15 patients at 2.4+/-0.5, 5 and 24 h after onset of ischemic stroke and compared with control blood samples. The 2.4-h blood samples were drawn before patients were treated either with tissue-type plasminogen activator (tPA) alone or with tPA plus Eptifibatide (the Combination approach to Lysis utilizing Eptifibatide And Recombinant tPA trial). Most genes induced in whole blood at 2 to 3 h were also induced at 5 and 24 h. Separate studies showed that the genes induced at 2 to 24 h after stroke were expressed mainly by polymorphonuclear leukocytes and to a lesser degree by monocytes. These genes included: matrix metalloproteinase 9; S100 calcium-binding proteins P, A12 and A9; coagulation factor V; arginase I; carbonic anhydrase IV; lymphocyte antigen 96 (cluster of differentiation (CD)96); monocarboxylic acid transporter (6); ets-2 (erythroblastosis virus E26 oncogene homolog 2); homeobox gene Hox 1.11; cytoskeleton-associated protein 4; N-formylpeptide receptor; ribonuclease-2; N-acetylneuraminate pyruvate lyase; BCL6; glycogen phosphorylase. The fold change of these genes varied from 1.6 to 6.8 and these 18 genes correctly classified 10/15 patients at 2.4 h, 13/15 patients at 5 h and 15/15 patients at 24 h after stroke. These data provide insights into the inflammatory responses after stroke in humans, and should be helpful in diagnosis, understanding etiology and pathogenesis, and guiding acute treatment and development of new treatments for stroke.

Chronic hypopituitarism after traumatic brain injury: risk assessment and relationship to outcome.

OBJECTIVE: Chronic pituitary dysfunction is increasingly recognized as a sequela of traumatic brain injury. We sought to define the incidence, risk factors, and neurobehavioral consequences of chronic hormonal deficiencies after complicated mild, moderate, or severe traumatic brain injury. METHODS: Patients aged 14 to 80 years were prospectively enrolled at the time of injury and assessed at 3 and 6 to 9 months after injury for hormonal function and neurobehavioral consequences. Major and minor (subclinical) hormonal deficiencies, including growth hormone deficiency (GHD) and growth hormone insufficiency (GHI), were identified. Acute injury characteristics, neurobehavioral, and quality of life measures were compared in patients with and without major hormonal deficits by the use of multivariate analysis. RESULTS: Out of 70 patients (mean age, 32 yr; median Glasgow Coma Scale score, 7; 19% women) tested at 6 to 9 months after injury, 15 (21%) had at least one major hormonal deficiency, 20 (29%) had minor deficiencies, and 30 (43%) had major and/or minor deficiencies. Patients with major deficiencies included 16% with GHD or GHI, 10.5% with hypogonadism, and 1.4% with diabetes insipidus. None of the patients required adrenal or thyroid replacement. At 6 to 9 months after injury, patients with major hormonal deficits had more abnormal acute computed tomographic findings (P = 0.014), greater acute and chronic body mass index (P < 0.01), and a worse Disability Rating Scale score (multivariate P = 0.04). Compared with the 59 growth hormone-sufficient patients, the 11 patients with GHD or GHI had worse Disability Rating Scale scores (multivariate P = 0.04), greater rates of depression, (90 versus 53%; multivariate P = 0.06), and worse quality of life in the Short Form-36 domains of energy and fatigue (multivariate P = 0.03), emotional well-being (multivariate P = 0.02), and general health (multivariate P = 0.07). CONCLUSION: Chronic hypopituitarism warranting hormone replacement occurs in approximately 20% of patients after complicated mild, moderate, or severe traumatic brain injury and is associated with more severe brain injuries and increased disability. GHD and GHI are also associated with increased disability, poor quality of life, and a greater likelihood of depression. The clinical significance of minor hormonal deficits, which occur in almost 30% of patients, warrants further study. Given that major deficiencies are readily treatable, routine pituitary hormonal testing within 6 months of injury is indicated for this patient population.